Alzheimer's disease (AD) is the most common dementia in the elderly and imposes a tremendous burden to patients' families and the society both financially and emotionally. Currently, there is no effective treatment available to cure the disease. Pathologically, AD is characterized by the presence of extracellular ?-amyloid (A?) plaques and intracellular tau-neurofibrillary tangles in selected brain regions including cerebral cortex and hippocampus. Multiple strategies targeting on A? generation and clearance are being pursued vigorously in an effort to reduce A? levels and A?- induced synaptic and neuronal toxicity. However, these attempts, including those using anti-A? immunotherapies, have not led to any FDA-approved drugs to treat AD, mainly due to toxic side effects and lack of efficacy. Despite these failures, anti-A?-based immunotherapies have made progress. Crenezumab, a humanized monoclonal antibody targeting both monomeric and oligomeric forms of A? by Genentech/Roche, inhibits A? aggregation and promotes A? disaggregation. Although it missed its primary endpoints in a lately completed Phase II clinical trial, crenezumab treatment in people with mild-to-moderate AD showed a trend toward slowing cognitive decline. Most recently, Biogen Idec has announced positive results from a Phase 1b clinical trial on its pipeline drug candidate aducanumab, a human monoclonal antibody that binds aggregated forms of A? with high affinity, and plans to carry out a phase III study. Therefore, anti- A? immunotherapies are highly promising and improved anti-A? therapeutic reagents can help bring such therapies into clinic. The purpose of this proposed project is to generate an advanced nano-antibody for reducing ?-amyloid (A?) levels and preventing A? plaque formation in AD. Nan- antibody (nAb) is a distinctive type of antibody fragment derived from camelid heavy-chain only antibody (HCAb). As a therapeutic candidate, nAb holds many superior properties that may enable some key improvement of current anti-A? reagents to help them succeed in clinical trials. In this proposal, we will develop engineered nano-antibodies that will bind A? and target it for degradation. We will test the efficacy of such anti-A? reagents in cell and mouse models of Alzheimer's disease. We expect that this engineered anti-A? nAbs to have higher A? binding affinity and greater A? reduction efficiency, but less toxic side effects compared to conventional antibodies.